Alzheimer's disease is a serious neurodegenerative illness with a cruel manifestation and few treatment options. Although much has been uncovered about the pathogenesis of familial Alzheimer's disease, little is known about the mechanisms that bring about the sporadic form of the disease that affects about 95% of Alzheimer's patients. Specifically, how is it that environmental and secondary genetic cues are able to trigger the same pathophysiologic events that occur when the direct proteins involved in these events become mutated? In this proposal, I hypothesize that oxidative stress, and specifically nitric oxide, may be capable of exacerbating and perhaps even triggering the same overproduction of amyloid-beta that is seen in familial Alzheimer's disease. Preliminary data shows that gamma-secretase, one of the proteases responsible for amyloid-beta production, is susceptible to nitric oxide-induced S-nitrosylation, and that nitric oxide is capable of increasing gamma-secretase activity. These results suggests a simple but powerful mechanism for how the oxidative stress seen in many conditions that promote sporadic Alzheimer's disease may directly increase amyloid-beta production. In order to further investigate this possibility, I have proposed a series of experiments that will help to elucidate as well as characterize the role of gammasecretase S-nitrosylation on the overall production of amyloid-beta. Using multiple gamma-secretase activity assays, these experiments will test the ability of S-nitrosylation to stimulate gamma-secretase activity. In addition, the specific mechanism of gamma-secretase S-nitrosylation will be determined using both exogenous and endogenous sources of nitric oxide. If the results of these experiments show that gamma-secretase S-nitrosylation plays a significant role in the production of amyloid-beta, this would be a major discovery in the Alzheimer's field. Furthermore, it would have significant implications for possible new therapeutic methods for treating and perhaps even preventing the disease. Alzheimer's disease is a neurodegenerative illness that affects about 24 million people across the globe. This proposal presents a novel idea about what may be triggering Alzheimer's disease, suggesting that Alzheimer's may be caused by increased oxidative stress, which may be capable of modifying an important player in the disease. The results of this research could lead to new ways of treating Alzheimer's disease, including new, more specific forms of antioxidant therapy.